The molecular basis of intervertebral disc degeneration

BackgroundIntervertebral disc (IVD) degeneration remains a clinically important condition for which treatment is costly and relatively ineffective. The molecular basis of degenerative disc disease has been an intense focus of research recently, which has greatly increased our understanding of the biology underlying this process.PurposeTo review the current understanding of the molecular basis of disc degeneration.Study designReview article.MethodsA literature review was performed to identify recent investigations and current knowledge regarding the molecular basis of IVD degeneration.ResultsThe unique structural requirements and biochemical properties of the disc contribute to its propensity toward degeneration. Mounting evidence suggests that genetic factors account for up to 75% of individual susceptibility to IVD degeneration, far more than the environmental factors such as occupational exposure or smoking that were previously suspected to figure prominently in this process. Decreased extracellular matrix production, increased production of degradative enzymes, and increased expression of inflammatory cytokines contribute to the loss of structural integrity and accelerate IVD degeneration. Neurovascular ingrowth occurs, in part, because of the changing degenerative phenotype.ConclusionsA detailed understanding of the biology of IVD degeneration is essential to the design of therapeutic solutions to treat degenerative discs. Although significant advances have been made in explaining the biologic mediators of disc degeneration, the inhospitable biochemical environment of the IVD remains a challenging environment for biological therapies.     

The influence of occupation on lumbar degeneration.

In many countries, back problems have been defined as occupational injuries. The belief underlying this injury model is that back symptoms are caused primarily by work-related mechanical factors that damage the structures of the spine, either through a single incident or repeated loading. Although the etiopathogenesis of degenerative findings in the disc and their relation to pain are poorly understood, changes in the disc are suspected of underlying many back symptoms. The focus of this article is on examining the relation between occupational factors and disc degeneration. Occupational factors suspected of accelerating spinal degeneration include accident-related trauma; heavy physical loading and materials handling, including lifting, bending, and twisting; prolonged sitting; and sustained nonneutral work postures and vehicular driving. There is evidence to suggest that occupational exposures have an effect on disc degeneration. However, these factors explain little of the variability in degeneration found in the adult population. Furthermore, the lack of a clear dose-response relation between time spent in various occupational loading conditions and degenerative findings adds to doubts about a strong causal link. The contribution of suspected occupational risk factors appears to be particularly modest when compared with familial influences, which reflect the combined effects of genes and early childhood environment. These findings challenge the dominant role assumed for occupational loading in disc degeneration and associated back problems, and suggest a more complex etiology.     

痤疮丙酸杆菌感染与椎间盘退变的研究进展

椎间盘退变的机制十分复杂,可能与椎间盘机械应力损伤、营养缺乏、炎症因子刺激等多种因素有关。近年来,不少学者在退变椎间盘组织内检测到痤疮丙酸杆菌,认为痤疮丙酸杆菌可引起椎间盘退变。笔者就痤疮丙酸杆菌感染与椎间盘退变相关文献作一综述,并归纳总结痤疮丙酸杆菌进入椎间盘途径以及引起椎间盘退变的机制,旨在为临床治疗椎间盘退变提供参考。     

Advances in Magnetic Resonance Imaging for the assessment of degenerative disc disease of the lumbar spine

The intervertebral disc is characterized by a tension-resisting annulus fibrosus, and a compression-resisting nucleus pulposus composed largely of proteoglycan. Both the annulus and the nucleus function in concert to provide the disc with mechanical stability. Early disc degeneration begins in the nucleus with proteoglycan depletion. Quantitative MRI techniques have been developed to non-invasively quantify the earliest degenerative changes that occur within the disc. Our ability to identify and quantify these early biochemical changes will provide a better understanding of the pathophysiology of disc degeneration and facilitate the study of interventions that aim to halt or reverse the degenerative process.     

Experimental instability in the rabbit lumbar spine

The authors performed mechanical, biochemical, and histologic analyses of changes in the rabbit lumbar spine occurring after instability had been induced by facet removal to find whether this intervention produced an experimental model for intervertebral disc degeneration. Sham operated animals and an unoperated control group were used for comparison. Half of the operated animals were housed under conditions to promote higher physical activity than the other animals housed individually in small cages. Acutely, the removal of facet joints increased the flexibility of intervertebral joints. Over the following year, this increase in flexibility was reduced to close to control levels in all groups of animals. Within the intervertebral discs, there was no significant change in proportions or solubility of collagen or proteoglycans after surgery, nor was there microscopic or macroscopic evidence of disc degeneration. The surgical procedure produced hypermobility of the spine, but there was a subsequent restabilization, and the intended disc degeneration was not produced. These findings indicate that some as yet unidentified soft tissue repair process, facilitated by activity, overcame the hypermobility created at surgery, so degenerative changes in the intervertebral discs did not result. We suggest that other animal models of disc degeneration may represent a failure of reparative response to acute injury.     

Basic science of spinal degeneration

This article summarizes recent advances in our understanding of spinal pathology and pain. Degeneration appears to start in the intervertebral discs, often before age 20 years, and can be distinguished from ‘normal’ ageing by the presence of physical disruption, typically in the form of annulus fissures, prolapse or endplate fracture. Disruption is ultimately mechanical, but frustrated attempts by a small population of disc cells to heal a large avascular matrix give rise to the typical biological features of disc degeneration. Genetic inheritance and ageing are important risk factors for disc degeneration because they can weaken the disc matrix, and hinder repair processes. Discogenic pain appears to arise from the disc periphery as a result of in-growing nerves being sensitized by soluble factors from activated disc and blood cells. A degenerated disc loses pressure in the nucleus and bulges radially outwards, like a flat tyre. This often leads to a transient segmental instability, which can be reversed by the growth of osteophytes around the margins of the vertebral body. Annulus collapse in severe disc degeneration transfers compressive load-bearing to the neural arch, leading to facet joint osteoarthritis, and possibly to degenerative scoliosis. The anterior vertebral body then becomes relatively unloaded, and consequent focal bone loss (exacerbated by systemic osteoporosis) increases the risk of anterior wedge deformities, and senile kyphosis. Future interventions may include physical therapy to aid disc healing, disc prostheses with no moving parts, and injection therapies to block pain pathways.     

Mechanical loading of the intervertebral disc: from the macroscopic to the cellular level

Purpose

Mechanical loading represents an integral part of intervertebral disc (IVD) homeostasis. This review aims to summarise recent knowledge on the effects of mechanical loads on the IVD and the disc cells, taking into consideration the changes that IVDs undergo during ageing and degeneration, from the macroscopic to the cellular and subcellular level.

Methods

Non-systematic literature review.

Results

Several scientific papers investigated the external loads that act on the spine and the resulting stresses inside the IVD, which contribute to estimate the mechanical stimuli that influence the cells that are embedded within the disc matrix. As disc cell responses are also influenced by their biochemical environment, recent papers addressed the role that degradation pathways play in the regulation of (1) cell viability, proliferation and differentiation and (2) matrix production and turnover. Special emphasis was put on the intracellular-signalling pathways, as mechanotransduction pathways play an important role in the maintenance of normal disc metabolism and in disc degenerative pathways.

Conclusions

Disc cells are exposed to a wide range of mechanical loads, and the biochemical environment influences their responses. Degeneration-associated alterations of the disc matrix change the biochemical environment of disc cells and also the mechanical properties of the disc matrix. Recent studies indicate that these factors interact and regulate disc matrix turnover.

     

The Twin Spine Study: Contributions to a changing view of disc degeneration

Background contextDisc degeneration was commonly viewed over much of the last century as a result of aging and “wear and tear” from mechanical insults and injuries. Thus, prevention strategies and research in lumbar degenerative changes and associated clinical conditions focused largely on mechanical factors as primary causes using an “injury model.” The Twin Spine Study, a research program on the etiology and pathogenesis of disc degeneration, has contributed to a substantial revision of this view of determinants of lumbar disc degeneration.PurposeTo provide a review of the methods and findings of the Twin Spine Study project.Study design/settingNarrative review of the Twin Spine Study.MethodsThe Twin Spine Study, which started in 1991, is a multidisciplinary, multinational research project with collaborators primarily in Canada, Finland, and the United States. The most significant investigations related to determinants of disc degeneration included occupational exposures, driving and whole-body vibration exposure, smoking exposure, anthropomorphic factors, heritability, and the identification of genotypes associated with disc degeneration.ResultsAmong the most significant findings were a substantial influence of heredity on lumbar disc degeneration and the identification of the first gene forms associated with disc degeneration. Conversely, despite extraordinary discordance between twin siblings in occupational and leisure-time physical loading conditions throughout adulthood, surprisingly little effect on disc degeneration was observed. Studies on the effects of smoking on twins with large discordance in smoking exposure demonstrated an increase in disc degeneration associated with smoking, but this effect was small. No evidence was found to suggest that exposure to whole-body vibration through motorized vehicles leads to accelerated disc degeneration in these well-controlled studies. More recent results indicate that the effect of anthropometric factors, such as body weight and muscle strength on disc degeneration, although modest, appear in this work to be greater than those of occupational physical demands. In fact, some indications were found that routine loading may actually have some benefits to the disc.ConclusionsThe once commonly held view that disc degeneration is primarily a result of aging and “wear and tear” from mechanical insults and injuries was not supported by this series of studies. Instead, disc degeneration appears to be determined in great part by genetic influences. Although environmental factors also play a role, it is not primarily through routine physical loading exposures (eg, heavy vs. light physical demands) as once suspected.     

Pathomechanics and clinical relevance of disc degeneration and annular tear: a point-of-view review.

Annular tear is a major cause of intervertebral disc degeneration that results in disabling back pain. Many of the stresses resulting in this type of lesion are common in the workplace: compression, torsion, compression combined with flexion, and vibration. Age-related disc degeneration begins early in adulthood, and progresses thereafter, altering disc morphology and mechanical properties in ways that predispose to disc herniation, and should not be misconstrued as "old age." Acute trauma may produce disc herniation whether or not there are predisposing factors, such as age-related degeneration, but disc herniation in the absence of acute injury requires the presence of preexisting degenerative changes.     

What is intervertebral disc degeneration, and what causes it?

STUDY DESIGN: Review and reinterpretation of existing literature. OBJECTIVE: To suggest how intervertebral disc degeneration might be distinguished from the physiologic processes of growth, aging, healing, and adaptive remodeling. SUMMARY OF BACKGROUND DATA: The research literature concerning disc degeneration is particularly diverse, and there are no accepted definitions to guide biomedical research, or medicolegal practice. DEFINITIONS: The process of disc degeneration is an aberrant, cell-mediated response to progressive structural failure. A degenerate disc is one with structural failure combined with accelerated or advanced signs of aging. Early degenerative changes should refer to accelerated age-related changes in a structurally intact disc. Degenerative disc disease should be applied to a degenerate disc that is also painful. JUSTIFICATION: Structural defects such as endplate fracture, radial fissures, and herniation are easily detected, unambiguous markers of impaired disc function. They are not inevitable with age and are more closely related to pain than any other feature of aging discs. Structural failure is irreversible because adult discs have limited healing potential. It also progresses by physical and biologic mechanisms, and, therefore, is a suitable marker for a degenerative process. Biologic progression occurs because structural failure uncouples the local mechanical environment of disc cells from the overall loading of the disc, so that disc cell responses can be inappropriate or "aberrant." Animal models confirm that cell-mediated changes always follow structural failure caused by trauma. This definition of disc degeneration simplifies the issue of causality: excessive mechanical loading disrupts a disc's structure and precipitates a cascade of cell-mediated responses, leading to further disruption. Underlying causes of disc degeneration include genetic inheritance, age, inadequate metabolite transport, and loading history, all of which can weaken discs to such an extent that structural failure occurs during the activities of daily living. The other closely related definitions help to distinguish between degenerate and injured discs, and between discs that are and are not painful.